There is increasing evidence that chronic stress can contribute to the initial or continued use of abused drugs, such as cocaine. Previous research in rodents has reported an increased sensitivity to the rewarding and locomotor responses to cocaine administration following exposure to repeated stress. Fewer reports have evaluated whether chronic stress also augments the negative component of cocaine use--the anxiety-like behaviors associated with cessation of cocaine administration. The proposed research will test the hypothesis that chronic stress augments the anxiety-like withdrawal behaviors associated with chronic cocaine administration through stress-induced alterations in mesocortical dopamine and glucocorticoid systems. Specific Aim 1 will investigate whether chronic stress enhances the anxiety-like withdrawal behaviors (the elevated plus maze and defensive burying task) following cocaine administration. Two neurochemical mechanisms that may mediate the potentiation by chronic stress of anxiety-like cocaine withdrawal behaviors will be investigated. Dopamine in the PFC is very responsive to stress and plays an integral role in the type of behaviors assessed during withdrawal from cocaine and in the development of behavioral sensitization to repeated cocaine administration. Therefore, Specific Aim 2 will correlate the release of dopamine in the PFC to the presence of the anxiety-like behaviors in chronically stressed or non-stressed rats. Glucocorticoids have been shown to mediate the effects of cocaine on stress-enhanced behavioral and dopaminergic responses. Specific Aim 3 will determine whether glucocorticoid synthesis mediates the anxiety-like withdrawal behaviors and the mesocortical alterations associated with the cessation of cocaine administration. If the severity of the anxiety-like withdrawal behaviors relates to chronic stress exposure, elucidating the mechanism through which stress alters PFC dopamine could provide potentially valuable information for decreasing the risk of chronic cocaine use in stressful environments.